Pentoxifylline-Induced Apoptosis in Chronic Lymphocytic Leukemia: New Insights into Molecular Mechanism
| Autor: | Roberta Napolitano, Serena De Matteis, Silvia Carloni, Delia Cangini, Alessandro Lucchesi, Pier Paolo Fattori, Eliana Valentina Liardo, Marianna Norata, Gerardo Musuraca |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Chronic lymphocytic leukemia Antineoplastic Agents Apoptosis Peripheral blood mononuclear cell Pentoxifylline 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Western blot Annexin hemic and lymphatic diseases Drug Discovery medicine Humans Cells Cultured Pharmacology Membrane Potential Mitochondrial TUNEL assay medicine.diagnostic_test Dose-Response Relationship Drug Chemistry NF-kappa B General Medicine medicine.disease Leukemia Lymphocytic Chronic B-Cell 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 030220 oncology & carcinogenesis Cancer research Leukocytes Mononuclear DNA fragmentation Drug Screening Assays Antitumor medicine.drug |
| Zdroj: | Mini reviews in medicinal chemistry. 18(3) |
| ISSN: | 1875-5607 |
| Popis: | Background Chronic lymphocytic leukemia (CLL) is an indolent B-lineage neoplasm, characterized by clonal expansion of CD5 positive B cells with constitutive activation of survival pathways including NF-kB. Pentoxifylline, a xanthine-derivative compound indicated for the treatment of microvascular disturbancies, has been suggested to have anti-proliferative and anti-metastatic activities in various types of cancer. In the present study we extend these data showing one of the potential molecular mechanisms through which Pentoxifylline may promote apoptosis in CLL clonal lymphocytes. Methods Peripheral blood mononuclear cells were isolated from 15 CLL patients 0 RAI stage and 15 healthy volunteers and treated for 24 and 48 hours with Pentoxifylline. Apoptosis induction was evaluated through Annexin V and TUNEL assays. Mitochondrial membrane potential depolarization analysis, active Caspase-3 assay, reactive oxygen species generation and Western Blot were assessed to further investigate the alterations induced by Pentoxifylline. Results We observed a statistically significant occurrence of apoptosis, DNA fragmentation and active Caspase-3 in lymphocytes from CLL patients compared to healthy volunteers after 48 hours of Pentoxifylline treatment. To clarify the molecular mechanism of the drug, we also evaluated the expression levels of NF-kB/p65 and its related proteins. In treated CLL cells, NF-kB/p65 was significantly decreased in comparison to normal cells, whereas we observed a less marked reduction of Bcl-2 expression. The treatment also induced a decrease of Mcl-1 in CLL cells with a greater down-regulation of the anti-apoptotic alternatively spliced isoform. Conclusion These findings showed that Pentoxifylline induced apoptosis in leukemic cells through a molecular mechanism that involves the NF-kB signaling. |
| Databáze: | OpenAIRE |
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